US3676433A - Improved process for the 5{60 ,6{60 -epoxidation of {66 {11 -double bonds - Google Patents
Improved process for the 5{60 ,6{60 -epoxidation of {66 {11 -double bonds Download PDFInfo
- Publication number
- US3676433A US3676433A US72490A US3676433DA US3676433A US 3676433 A US3676433 A US 3676433A US 72490 A US72490 A US 72490A US 3676433D A US3676433D A US 3676433DA US 3676433 A US3676433 A US 3676433A
- Authority
- US
- United States
- Prior art keywords
- alpha
- dione
- ketal
- bisethylene
- epoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000000034 method Methods 0.000 title claims abstract description 49
- 238000006735 epoxidation reaction Methods 0.000 title claims abstract description 16
- 150000003431 steroids Chemical class 0.000 claims abstract description 34
- 239000002253 acid Substances 0.000 claims abstract description 17
- XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- 150000004965 peroxy acids Chemical class 0.000 claims abstract description 10
- 230000000707 stereoselective effect Effects 0.000 claims abstract description 9
- 239000006172 buffering agent Substances 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000005977 Ethylene Substances 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 6
- -1 methyl 3,11-diketo-5,17(20)-pregnadien-21-oate Chemical compound 0.000 claims description 6
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 4
- 125000000468 ketone group Chemical group 0.000 claims description 4
- MNRHZPCIEGLWGK-LEKSSAKUSA-N pregn-5-ene-3,20-dione Chemical compound C1C=C2CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 MNRHZPCIEGLWGK-LEKSSAKUSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- HUCNOYBFZPBCKM-RKFFNLMFSA-N (8r,9s,10r,13s,14s)-17-acetyl-10,13-dimethyl-1,2,4,7,8,9,11,12,14,15-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C1C=C2CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC=C(C(=O)C)[C@@]1(C)CC2 HUCNOYBFZPBCKM-RKFFNLMFSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 229960003328 benzoyl peroxide Drugs 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 235000011056 potassium acetate Nutrition 0.000 description 4
- FPHIYNDIWHMUMI-CYPDMGDPSA-N (1S,2R,7R,9S,11S,12S,15S,16S)-15-acetyl-2,16-dimethyl-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadecan-5-one Chemical compound O1[C@]23[C@@H]1C[C@H]1[C@@H]4CC[C@H](C(C)=O)[C@]4(CC[C@@H]1[C@]3(CCC(C2)=O)C)C FPHIYNDIWHMUMI-CYPDMGDPSA-N 0.000 description 3
- 239000005909 Kieselgur Substances 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000010936 aqueous wash Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 150000004967 organic peroxy acids Chemical class 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000000538 analytical sample Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- MEFKFJOEVLUFAY-UHFFFAOYSA-N (2,2,2-trichloroacetyl) 2,2,2-trichloroacetate Chemical compound ClC(Cl)(Cl)C(=O)OC(=O)C(Cl)(Cl)Cl MEFKFJOEVLUFAY-UHFFFAOYSA-N 0.000 description 1
- XIIAYQZJNBULGD-UHFFFAOYSA-N (5alpha)-cholestane Natural products C1CC2CCCCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 XIIAYQZJNBULGD-UHFFFAOYSA-N 0.000 description 1
- MLNZCTSOJJGHSQ-CVHNGYJVSA-N (8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-1,2,4,5,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one Chemical compound CC([C@H]1CC[C@H]2[C@@H]3C=CC4CC(CC[C@]4(C)[C@H]3CC[C@]12C)=O)=O MLNZCTSOJJGHSQ-CVHNGYJVSA-N 0.000 description 1
- OTVRYZXVVMZHHW-FNOPAARDSA-N (8s,9s,10r,13r,14s,17r)-3-chloro-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthrene Chemical compound C1C=C2CC(Cl)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 OTVRYZXVVMZHHW-FNOPAARDSA-N 0.000 description 1
- ZKFNOUUKULVDOB-UHFFFAOYSA-N 1-amino-1-phenylmethyl phosphonic acid Chemical compound OP(=O)(O)C(N)C1=CC=CC=C1 ZKFNOUUKULVDOB-UHFFFAOYSA-N 0.000 description 1
- VHRSUDSXCMQTMA-UHFFFAOYSA-N 11,17-dihydroxy-17-(2-hydroxyacetyl)-6,10,13-trimethyl-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthren-3-one Chemical compound CC12C=CC(=O)C=C1C(C)CC1C2C(O)CC2(C)C(O)(C(=O)CO)CCC21 VHRSUDSXCMQTMA-UHFFFAOYSA-N 0.000 description 1
- MYYIMZRZXIQBGI-HVIRSNARSA-N 6alpha-Fluoroprednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3C[C@H](F)C2=C1 MYYIMZRZXIQBGI-HVIRSNARSA-N 0.000 description 1
- VHRSUDSXCMQTMA-PJHHCJLFSA-N 6alpha-methylprednisolone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- HYRKAAMZBDSJFJ-LFDBJOOHSA-N Paramethasone acetate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)COC(C)=O)(O)[C@@]2(C)C[C@@H]1O HYRKAAMZBDSJFJ-LFDBJOOHSA-N 0.000 description 1
- SCKXCAADGDQQCS-UHFFFAOYSA-N Performic acid Chemical class OOC=O SCKXCAADGDQQCS-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- XIIAYQZJNBULGD-LDHZKLTISA-N cholestane Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 XIIAYQZJNBULGD-LDHZKLTISA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 229960000618 fluprednisolone Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000010952 in-situ formation Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229940064748 medrol Drugs 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- 229960003846 melengestrol acetate Drugs 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 229940063222 provera Drugs 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Definitions
- the process of this invention comprises reacting a steroid containing an isolated 5,6-double bond with peroxytrifluoroacetic acid or peroxytrichloroacetic acid in an organic solvent of low polarity which promotes intramolecular hydrogen bonding in the peracid molecule, and in the presence of a basic buffering agent, to obtain the corresponding 5a,6a-epoxide.
- An important characteristic of many pharmacologically active steroids is the presence of a methyl or halogen substituent at the a-position.
- the process of this invention provides an improved method for obtaining important 5a,6a-expoxide intermediates leading to these useful compounds.
- peroxytrifluoroacetic acid prepared by the addition of trifluoroacetic acid to hydrogen peroxide, and its unique property as an oxidizing agent were first described by W. D. Emmons and A. F. Ferris, J. Am. Chem. Soc. 75, 4623 (1953).
- peroxytrihaloacetic acids for the stereoselective epoxidation of double bonds in steroidal molecules has not hitherto been known and, in addition, the effects of solvents on the stereoselective course of the epoxidation with these acids is also a new and novel part of the present invention.
- Steroids containing the 5a,6a-epoxide function are important intermediates in the synthesis of 6-alkyl an'd 6-halosteroids such as Medrol (6a-methylprednisolone), Melenges-trol acetate l6-methylenel 7a-acetoxy-6-methyl-4,6- pregnadiene-3,20-dione), Provera (6a-methyl-l7a-acetoxyproges-terone), Alphadrol (Ga-fluoroprednisolone), Haldrone (6a-fluoro- 1 a-methyl-l 113, 1 711,2 1 -trihydroxyl ,4- pregnadiene-3,20-dione ZI-acetate) and many others well known in the art.
- Medrol (6a-methylprednisolone)
- Provera (6
- the high yields of the desired 5a,6a-epoxides obtained by the process of this invention are brought about by epoxidizing a A -steroid with peroxytrifluoroacetic acid or peroxytrichloroacetic acid in an organic solvent of low polarity which promotes intramolecular hydrogen bonding within the peracid molecule,
- the reaction is carried out in the presence of a basic buffering agent to prevent decomposition of acid sensitive substrates, for example, to prevent hydrolysis of 3- and -ketal groups when present in the starting material and to prevent opening of the oxirane ring.
- the improved process of this invention is generally applicable to any steroid having an isolated (unconjugated) double bond at the 5,6-position of the steroid molecule. They can also possess keto, hydroxy, alkyl, acyloxy, halo, cyclopropyl, cyclic alkylene ketal and other groups attached to the steroid ring structure, especially at positions 3, 4, 7, 9, l 1, 12, 14, 16, 17, 20, and 21 and they can have other double bonds which are unreactive under the conditions of the process of the present invention.
- the selected starting steroid having an unconjugated double bond at the 5,6-position is dissolved, dispersed or suspended in an organic solvent compatible with. the stereo-selective formation of the desired 5a,6a-epoxide of the selected starting material.
- Organic solvents which are stereoselective to 5a,6a-epoxide formation are those of low polarity which promote intramolecular hydrogen bonding within the selected peracid molecule.
- solvents are representative of those which can be used, for example, methylene chloride, benzene, chlorobenzene, toluene, chloroform, bromobenzene, odichlorobenzene, xylene, ethylene dichloride, mixtures thereof and the like.
- a basic buffering agent is added and the reaction mixture is cooled to a temperature below 0 C.; -l0 C. to -30 C. is preferred.
- the mixture is then treated with a solution of peroxytrifluoroacetic acid or peroxytrichloroacetic acid (prepared in situ in an organic solvent medium of low polarity which promotes intramolecular hydrogen bonding within the selected peracid). The temperature is maintained below 0 C.
- Basic buffering agents which can be used include, for example, sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, disodium hydrogen phosphate, etc.
- the reaction mixture is made basic by the addition of dilute sodium or potassium hydroxide, the organic phase is separated from the aqueous phase, washed to a neutral pH, filtered and then removed by distillation to give the desired 5a,6a-epoxide.
- the epoxide thus obtained is further purified if desired by crystallization from a suitable organic solvent such as acetone, acetone-water, ether, ethyl acetate, methylene chloride, benzene and the like.
- Preparation 1 peroxytriiluoroacetic acid A solution of 8.5 ml. of trifluoroacetic anhydride in 10 ml. of methylene chloride is cooled to about 0 C. and 2 ml. of percent hydrogen peroxide is added. The solution is stirred at 0 C. for about 15 minutes and then allowed to reach room temperature. For storage purposes the solution of peroxytrifluoroacetic acid, thus obtained, is kept at or below 0 C.
- Preparation 2 peroxytrichloroacetic acid
- a solution of 9.0 ml. of trichloroacetic anhydride in 10 ml. of methylene chloride is cooled to 0 C. and treated with 90 percent hydrogen peroxide in the manner described in Preparation 1, above, to obtain a solution of peroxytrichloroacetic acid.
- the solution is advantageously kept at about 0 C. or below.
- Example 1 5a,6a-epoxy-l la-acetoxypregnane-B,20-dione 3,20-bisethylene ketal
- the solution of peroxytrifluoroacetic acid prepared in Preparation 1 above, is diluted with ml. of methylene chloride, cooled to about -20 C. and added slowly to the reaction mixture while maintaining the temperature at about -20 C. The progress of the reaction is followed by thin layer chromatography (TLC).
- TLC thin layer chromatography
- the reaction mixture is made basic by the addition of dilute sodium hydroxide solution to a pH of about 9 and stirred for about 1 hour at l2-l 4 C.
- the organic phase is then separated and washed to a neutral pH.
- Each aqueous wash is back washed with chloroform and the chloroform is added to the organic phase.
- the combined organic phase and washes are stirred with 0.3 g. of diatomaceous earth (Celite), filtered and the filter cake is washed with three 5 ml. portions of chloroform.
- the filtrate and washes are combined and concentrated to dryness under vacuum at about 60 C. to give 9.2 g. (96.6 percent yield) of 5a,6aepoxy-l la-acetoxypregnane-3,ZO-dione 3,20- bisethylene ketal; m.p. 248-260 C.; [(11 59.
- Example 2 5a,6a-epoxypregnane-3,20-dione 3,20-bisethylene ketal
- a reaction mixture of8 g. (0.02 moles) of 5-pregnene-3,20- dione 3,20-bisethylene ketal, 19.6 g. (0.2 moles) of anhydrous potassium acetate, 52 ml. of chloroform (dry) and 52 ml. of chlorobenzene (dry) is cooled to about C. with stirring.
- the solution of peroxytrifluoroacetic acid prepared in Preparation 1, above, is diluted with 100 ml. of methylene chloride, cooled to about 20 C. and added slowly to the reaction mixture while maintaining the temperature at about 20 C. The progress of the reaction is followed by thin layer chromatography (TLC).
- TLC thin layer chromatography
- the reaction mixture is made basic by the addition of dilute sodium hydroxide solution to a pH of about 9 and stirred for about 1 hour at l2-l4 C.
- the organic phase is then separated and washed to a neutral pH.
- Each aqueous wash is back washed with chloroform and the chloroform is added to the organic phase.
- the combined organic phase and washes are stirred with 0.3 g. of diatomaceous earth (Celite), filtered and the filter cake is washed with three 5 ml. portions of chloroform.
- the filtrate and washes are combined and concentrated to dryness under vacuum at about 60 C. to give 8.14 g.
- Example 3 5a,6a-epoxy-1 lfl-hydroxypregnane-3,20-dione 3,20-bisethylene ketal
- a reaction mixture of 4.2 g. (0.01 moles) of l lB-hydroxy-S- pregnene-3,20-dione 3,20-bisethylene ketal, 9.65 g. (0.1 moles) of anhydrous potassium acetate, 26 ml. of chloroform (dry) and 26 ml. of chlorobenzene (dry) is cooled to about -20 C. with stirring.
- the solution of peroxytrifluoroacetic acid prepared in Preparation 1, above, is diluted with 50 ml. of methylene chloride, cooled to about 20 C. and added slowly to the reaction mixture while maintaining the temperature at about 20 C. The progress of the reaction is followed by thin layer chromatography (TLC).
- TLC thin layer chromatography
- reaction mixture is made basic by the addition of dilute sodium hydroxide solution to a pH of about 9 and stirred for about 1 hour at l2-l4 C.
- the organic phase is then separated and washed to a neutral pH. Each aqueous wash is back washed with chloroform and the chloroform is added to the organic phase.
- the combined organic phase and washes are stirred with 1.5 g.
- Example 4 5a,6a-epoxy-3fl-hydroxyl 6-pregnen-20-one Following the procedure of Example 1 above, 3fl-hydroxy- 5 ,l6-pregnadien-20-one is epoxidized to obtain 5a,6a-epoxy- 3,8-hydroxyl 6-pregnen-20-one.
- Example 5 5a,6a-epoxy-3B-acetoxyl 6-pregnen-20-one Following the procedure of Example 1 above, 3,8-acetoxy- 5,l6-pregnadien-20-one is epoxidized to obtain 5a,6a-epoxy- 3B-acetoxyl 6-pregnen-20-one.
- Example 6 methyl 5a,6a-epoxy-3,l l-diketo-l 7( 20)-pregnen- 2 l-oate 3-ethylene ketal
- methyl 3,] ldiketo-5,l7(20)-pregnadien-2l-oate 3-ethylene ketal is epoxidized to obtain methyl 5a,6a-epoxy-3,l l-diketo-l 7(20)- pregnen-2 l-oate 3-ethylene ketal.
- EXAMPLE 7 5a,6a-epoxy-l7a-hydroxypregnane-3,20-dione 3,20-bisethylene ketal Following the procedure of Example 1 above, l7a-hydroxy- 5-pregnene-3,20-dione 3,20-bisethylene ketal is epoxidized to obtain 5a,6a-epoxy-l7a-hydroxypregnane-3,20-dione 3,20- bisethylene ketal.
- EXAMPLE 8 5a,6a-epoxyl 7a-acetoxypregnane-3 ,20-dione 3,20-bisethylene ketal Following the procedure of Example 1 above, l7a-acetoxy- 5-pregnene-3,20-dione 3,20-bisethylene ketal is epoxidized to obtain 5a,6a-epoxyl 7a-acetoxypregnane-3,20-dione 3 ,20- bisethylene ketal.
- EXAMPLE 9 5a,6a-epoxy-l l B-hydroXy-2 l -acetoxyl 6- pregnene-3,20-dione 3,20-bisethylene ketal
- 1 IB-hydroxy- 21-acetoxy-5 l 6-pregnadiene-3 ,20-dione 3 ,20-bisethylene ketal is epoxidized to obtain 5a,6a-epoxy-l lB-hydroxy-Zlacetoxyl 6-pregnene-3,20-dione 3,20-bisethylene ketal.
- EXAMPLE l0 5a,6a-epoxy-l6-pregnene-3,20-dione 3,20- bisethylene ketal
- 5a,6a-epoxy-l6-pregnene-3,20-dione 3,20- bisethylene ketal is epoxidized to obtain 5a,6a-epoxy-l6-pregnene-3,20-dione 3,20-bisethylene ketal.
- organic solvent is selected from the group consisting of methylene chloride, benzene, chlorobenzene, toluene, chloroform,
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US7249070A | 1970-09-15 | 1970-09-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3676433A true US3676433A (en) | 1972-07-11 |
Family
ID=22107932
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US72490A Expired - Lifetime US3676433A (en) | 1970-09-15 | 1970-09-15 | Improved process for the 5{60 ,6{60 -epoxidation of {66 {11 -double bonds |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US3676433A (en, 2012) |
| DE (1) | DE2145594A1 (en, 2012) |
| FR (1) | FR2107655A5 (en, 2012) |
| GB (1) | GB1301808A (en, 2012) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6764545B2 (en) * | 2000-12-12 | 2004-07-20 | Ajinomoto Co., Inc. | Production method of epoxide crystal |
| US6841665B2 (en) | 2000-02-18 | 2005-01-11 | The University Of Hong Kong | Method for synthesizing 5β, 6β-epoxides of steroids by a highly β-selective epoxidation of ΔΔ5-unsaturated steroids catalyzed by ketones |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3547913A (en) * | 1958-10-01 | 1970-12-15 | Merck & Co Inc | 16beta-methyl-16alpha,17alpha-epoxy pregnenolone and the 3-acylates thereof |
-
1970
- 1970-09-15 US US72490A patent/US3676433A/en not_active Expired - Lifetime
-
1971
- 1971-09-01 GB GB4081671A patent/GB1301808A/en not_active Expired
- 1971-09-13 DE DE19712145594 patent/DE2145594A1/de active Pending
- 1971-09-14 FR FR7133113A patent/FR2107655A5/fr not_active Expired
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3547913A (en) * | 1958-10-01 | 1970-12-15 | Merck & Co Inc | 16beta-methyl-16alpha,17alpha-epoxy pregnenolone and the 3-acylates thereof |
Non-Patent Citations (1)
| Title |
|---|
| Spero et al., J. Am. Chem. Soc. Vol. 78 (1956) page 6213 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6841665B2 (en) | 2000-02-18 | 2005-01-11 | The University Of Hong Kong | Method for synthesizing 5β, 6β-epoxides of steroids by a highly β-selective epoxidation of ΔΔ5-unsaturated steroids catalyzed by ketones |
| US6764545B2 (en) * | 2000-12-12 | 2004-07-20 | Ajinomoto Co., Inc. | Production method of epoxide crystal |
Also Published As
| Publication number | Publication date |
|---|---|
| GB1301808A (en, 2012) | 1973-01-04 |
| DE2145594A1 (de) | 1972-03-16 |
| FR2107655A5 (en, 2012) | 1972-05-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US2752369A (en) | Oxidation of steroid-enamines | |
| US2819264A (en) | Steroid intermediates | |
| US2831003A (en) | Cycloborate esters of 16alpha, 17alpha-dihydroxy steroids | |
| US3682983A (en) | Preparation of {66 {11 {11 -17 ethinyl steroids | |
| US3676433A (en) | Improved process for the 5{60 ,6{60 -epoxidation of {66 {11 -double bonds | |
| US2769824A (en) | Hydroxylation of delta-pregnenes | |
| Bowers et al. | Steroids—CXXI synthesis of halogenated steroid hormones: 6α-fluoro cortical hormones a new class of powerful corticoids | |
| US3485852A (en) | 6-halo-6-dehydro-progesterones | |
| US2951074A (en) | C14 cortical steroids and methods of preparing same | |
| US3065228A (en) | Process for the production of delta5-androstene-19-ol and delta5-pregnene-19-ol compounds | |
| US2878246A (en) | Preparation of 6-methyl steroids of the pregnane series from diosgenin | |
| US2662854A (en) | Photochemical preparation of 17, 20-hydroxy-ketones of the pregnane series | |
| US2867631A (en) | 6-methylated and 11-oxygenated-17 alpha-hydroxy-21-fluoro 4-pregnene 3, 20 diones | |
| US3501513A (en) | Preparation of 17-desoxy steroids from corresponding 17alpha,21-dihydroxy - 20 - oxo steroids and 21-esters thereof | |
| US3528999A (en) | Substituted methylene steroids and their preparation | |
| US2984678A (en) | 14alpha-hydroxy hydrocortisone, cortisone and derivatives | |
| US3290296A (en) | Process for the production of iodohydrins or of cyclic ethers derived therefrom | |
| US3282929A (en) | Method for preparation of aromatic a ring steroids | |
| US3766225A (en) | Novel process for preparing steroid halohydrins and vinyl halides | |
| US3014936A (en) | 15-dehydro-cortical hormones | |
| US3697510A (en) | Novel preparation of pregnanes | |
| US3138589A (en) | Process for the production of 6-halo-3-keto-delta4, 6-steroids | |
| US3046285A (en) | 6-cyano cortical hormones | |
| US3194831A (en) | 18-nor-d-homo androstanes | |
| US2904546A (en) | delta4-3keto 14alpha-15alpha-oxido pregnenes |